42 research outputs found
Defective FoxP3+ Treg cell differentiation in the gut of Type 1 Diabetic patients
Environmental factors that act at the intestinal level such as diet, drugs, and microflora have a high impact on the pathogenesis of autoimmune Type 1 Diabetes (T1D), but it is still unclear how the gut milieu affects autoimmunity outside the intestine. Here we show that peripheral FoxP3+ Treg cell differentiation, a mechanism that takes place in the gut and is crucial to maintain systemic immune tolerance, is impaired in T1D patients. These results provide the first evidence that gut mucosa alteration could predispose to autoimmune T1D by affecting systemic immune regulation
Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients
Peripheral lymph nodes contain migratory and resident innate lymphoid cell populations
Tissue residency is considered a defining feature of the innate lymphoid cell (ILC) populations located within mucosal and adipose tissues. ILCs are also present within all lymphoid tissues, but whether ILCs migrate between lymphoid and nonlymphoid sites and in what context is poorly understood. To determine whether migratory ILCs exist within peripheral lymph nodes (LNs), we labeled all cells within the brachial LN (bLN) of transgenic mice expressing a photoconvertible fluorescent protein by direct exposure to light. Tracking of cellular changes in the labeled LN revealed the gradual migration of new ILCs into the tissue, balanced by egress of ILCs dependent on sphingosine-1-phosphate receptors. Most of the migratory ILCs were ILC1s, entering LNs directly from the circulation in a CD62L- and CCR7-dependent manner and thus behaving like conventional natural killer (cNK) cells. Upon egress, both ILC1s and cNK cells were found to recirculate through peripheral LNs. A distinct population of migratory ILC2s were detected in the LN, but most of the ILC3s were tissue resident. Functionally, both migratory and resident ILC1s within LNs were able to rapidly produce IFN-γ to support the generation of robust TH1 T cell responses after immunization. Thus, migratory and resident ILC populations exist within peripheral LNs, with ILC1s, akin to cNK cells, able to traffic into these tissues where they can contribute to the initiation of adaptive immunity
X-linked cataract and Nance-Horan syndrome are allelic disorders
Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved
Cancer data quality and harmonization in Europe: the experience of the BENCHISTA Project – international benchmarking of childhood cancer survival by stage
IntroductionVariation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers.MethodsPBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created.Results67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)].ConclusionDifferences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans
Observation of gravitational waves from the coalescence of a 2.5−4.5 M⊙ compact object and a neutron star
Ultralight vector dark matter search using data from the KAGRA O3GK run
Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM
The role of IL-1beta in intestinal inflammation
Although very high levels of IL 1β are present in the intestines of patients suffering from Inflammatory Bowel Diseases (IBD), little is known about the contribution of IL 1β to intestinal pathology. In the work presented in this thesis, I used several mouse models of chronic intestinal inflammation to address the role of IL 1β in driving innate and adaptive immune pathology in the intestine. My results showed that IL 1β promotes innate immune pathology in Helicobacter hepaticus triggered innate intestinal inflammation, by augmenting the recruitment of granulocytes and the accumulation and activation of a population of IFN γ and IL 17A producing innate lymphoid cells (ILC). To specifically investigate the role of IL 1R signaling on pathogenic T cell responses in the intestine, I used a T cell transfer colitis model. My results demonstrated a key role for IL 1R signals in promoting the accumulation and survival of pathogenic CD4+ T cells in the colon, particularly CD4+ IL 17A+ Th17 cells. Finally, because mutations in the NOD2 gene have been strongly associated with susceptibility to IBD, I investigated the contribution of NOD2 in the H.hepaticusinduced innate immune IBD model. I found that NOD2 expression was significantly increased in the inflamed colon. Furthermore, my preliminary studies suggested that NOD2 played a pro inflammatory role in innate immune colitis, but that NOD2 had little impact on H.hepaticus colonization of the mouse intestine. In summary, my results identify multiple mechanisms through which IL 1β promotes intestinal pathology and suggesting that targeting IL 1β, or innate immune receptors, may represent a useful therapeutic approach in IBD.</p
The role of IL-1beta in intestinal inflammation
Although very high levels of IL-1B are present in the intestines of patients suffering from Inflammatory Bowel Diseases (IBD) little is known about the contribution of IL- 1B to intestinal pathology. In the work presented in this thesis, I used several mouse models of chronic intestinal inflammation to address the role of IL-lB in driving innate and adaptive immune pathology in the intestine. My results showed that IL- 1B promotes innate immune pathology in Helicobacter hepaticus-triggered innate intestinal inflammation, by augmenting the recruitment of granulocytes and the accumulation and activation of a population of IFN-y- and IL-17A-producing innate lymphoid cells (ILC). To specifically investigate the role of IL-1R signaling on pathogenic T cell responses in the intestine, I used a T cell transfer colitis model. My results demonstrated a key role for IL-1R signals in promoting the accumulation and survival of pathogenic CD4+ T cells in the colon, particularly CD4+ IL-17A+ Th17 cells. Finally, because mutations in the NOD2 gene have been strongly associated with susceptibility to IBD, 1 investigated the contribution of NOD2 in the H.hepaticus- induced innate immune IBD model. I found that NOD2 expression was significantly increased in the inflamed colon. Furthermore, my preliminary studies suggested that NOD2 played a pro-inflammatory role in innate immune colitis, but that NOD2 had little impact on H.hepaticus colonization of the mouse intestine. In summary, my results identify multiple mechanisms through which IL-lB promotes intestinal pathology and suggesting that targeting IL-lB, or innate immune receptors, may represent a useful therapeutic approach in IBD.EThOS - Electronic Theses Online ServiceGBUnited Kingdo